Vaccination can be greatly improved by relying on a mechanism used by the mucosal immune system to sample antigens from the small intestine: transcytosis by M cells overlying Peyer's Patches. These specialized cells appear to use specific uptake and transport of microbes and particles to the lymphoid tissue, stimulating mucosal immune responses. We have identified several receptors with highly restricted expression in Peyer's Patch follicle associated epithelium (FAE) and the epithelium overlying nasal associated lymphoid tissue (NALT). In this proposal, we will test the feasibility of targeting these M cell receptors for the delivery of vaccine antigens to mucosal lymphoid tissue, using synthetic ligands specific to each of three different receptor proteins. In our Phase I studies, we propose to (1) develop short peptide ligands to these receptors using phage display selection, (2) test the ability of these ligands to bind specifically to the receptors in vitro and in vivo, and (3) assess the efficiency of these ligands in targeting the transcytosis of macromolecules and particles across the epithelium. The development of successful targeting ligands would comprise a novel platform for the development of synthetic vaccines, especially for the induction of mucosal immunity against agents such as influenza.